Erythropoietin (EPO) is a glycoprotein (hormone) that stimulates the induction of differentiation of erythroid stem cells and promotes the production of erythrocytes. Approximately 90% thereof is produced in the kidney.
Hypoxia inducible factor (HIF) is known as a factor promoting the transcription of the erythropoietin gene. HIF is a protein consisting of a heterodimer having an oxygen-regulated subunit α (HIF-α) and a constitutively expressed subunit β (HIF-β). On the other hand, GATA factors such as GATA2 and GATA3 are known as factors suppressing the transcription of the erythropoietin gene. The GATA factors are proteins binding to a GATA sequence located upstream of the erythropoietin gene. In the presence of normal oxygen, proline hydroxylase (PHD) hydroxylates proline of HIF-α, which is then degraded by ubiquitination through binding to von Hippel-Lindau (VHL). In this state, GATA3 therefore works predominantly to suppress the transcription of the erythropoietin gene. Under hypoxia, oxygen, which serves as a substrate of PHD, is insufficient. HIF-α is therefore neither hydroxylated by PHD nor degraded. In this state, HIF therefore works predominantly to promote the transcription of the erythropoietin gene.
It is known that the transcription of the erythropoietin gene is suppressed in chronic inflammations such as collagen diseases (chronic rheumatoid arthritis, systemic lupus erythematosus, etc.) and chronic infections (tuberculosis, infective endocarditis, hepatic abscess, etc.). Specifically, inflammatory cytokines such as interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) are released due to the chronic inflammations. The inflammatory cytokines thus released directly suppress erythrocyte production, while increasing the binding activity of the GATA factors, which bind to the upstream region of the erythropoietin gene, and thereby suppressing erythropoietin production. As a result, erythrocyte production is reduced so that symptoms of anemia are manifested. Also, it is known that erythropoietin production is similarly reduced in diseases such as chronic renal failure and hypothyroidism. Replacement therapy based on the administration of genetically recombinant human erythropoietin is usually used for treating anemia in such diseases or improving the symptoms of the diseases. Unfortunately, erythropoietin preparations, however, are expensive and require frequent doses of injection.
Recently, triazolopyridine compounds having a PHD inhibitory effect and the induction of erythropoietin production by these triazolopyridine compounds have been reported (patent document 1).
The present inventors have also reported that: indoxyl sulfate (IS), one of uremic toxins, promotes the expression of GATA3; and the adsorption and elimination of IS using active carbon (Kremezin) enhance the expression of endogenous erythropoietin (patent document 2).